This is a Phase Ib/II, open-label, multi-center, competitive enrollment and dose-escalation study of ALT-801 combined with cisplatin. The purpose of this study is to evaluate the safety, determine the Maximum-Tolerated Dose (MTD), and characterize the pharmacokinetic profile of ALT-801 given with cisplatin in patients who are chemotherapy naïve and have metastatic melanoma that is considered surgically incurable. The anti-tumor responses of ALT-801 with cisplatin will also be assessed in this trial.

Intravenous infusions; 2 treatment courses; 2 treatment cycles for each course; 70mg/m2 on day 1 of cycle 1 for each course

Biological: ALT-801

Intravenous infusions; cycle 1: day 3 and 5; cycle 2: day 1, 3 and 5; nine day rest period between cycles; seven day recovery period between courses

Stage 1: dose escalation (0.04 mg/kg, 0.06 mg/kg, 0.08 mg/kg)

Stage 2: dose expansion (dose at MTD)

Detailed Description:

Most current cancer treatment strategies involve the use of chemotherapeutic or biological drugs that exhibit variable efficacy and considerable toxicity. The limitations are often the result of the adverse side effects of the therapeutic drug on normal tissues. One approach to control these effects is to target the therapy to the tumor site. Of the identified tumor antigens, the human p53 tumor suppressor protein is overexpressed in a wide range of human malignancies. p53 is an intracellular tumor suppressor protein that acts to arrest the proliferation of cells. When mutated, it loses its ability to suppress abnormal proliferation and exhibits a longer half-life than the wild-type protein, allowing for its accumulation in tumors. In addition, p53 overexpression correlates with tumor transformation and aggression and is associated with lower overall survival rates and resistance to chemotherapeutic intervention in cancer patients. Therefore, p53 appears to be a marker for a considerable number of human malignancies and represents a good target for immunotherapeutics. However, p53 cannot be used as a target for antibodies because it is not displayed independently on the cell surface. Instead, the p53 protein is processed intracellularly into peptide fragments that are then displayed on the cell surface in the context of MHC. These peptide/MHC complexes are recognized by T-cells via their T-cell receptors (TCRs). Recently it has been confirmed that a p53 peptide fragment is significantly elevated in a wide range of human tumor tissues, particularly in melanoma, renal, lung, breast, colorectal, and osteosarcoma cancers. As a result, the feasibility of using soluble TCRs to target therapies against tumor cells that overexpress p53 is being investigated.

Interleukin-2 (IL-2) is a well-characterized growth factor for immune effector cells which play critical roles in tumor control and rejection. As a result, recombinant human IL-2 (e.g., Proleukin®, Chiron Novartis) has been approved for treatment of metastatic melanoma and renal cell carcinoma. IL-2 treatment provides significant benefit to a subset of patients with some maintaining durable responses for over ten years post-treatment. However, the major drawbacks of IL-2 therapy are its limited half-life and severe systemic toxicity. Hence, the use of high dose IL-2 is limited to specialized programs with experienced personnel, and it is generally offered to patients who are responsive and have excellent organ function. The low dose IL-2 treatment, while less toxic and more convenient, produces lower response rates and appears to be less effective in treating metastatic tumors. Thus, there is a critical need for innovative strategies that enhance the effects of IL-2 or reduce its toxicity without compromising clinical benefit. Targeted approaches to concentrate therapeutic cytokines, such as IL-2, at the tumor sites that express p53 could provide considerable advantages over current treatment.

The study drug, ALT-801, is a biologic compound composed of interleukin-2 (IL-2) genetically fused to a humanized soluble T-cell receptor directed against the p53-derived peptides expressed on tumor cells. This study is to evaluate whether directing IL-2 activity using ALT-801 to the patient's tumor sites that overexpress p53 results in clinical benefits if the ALT-801 treatment is given with cisplatin.

Platinum-based analogues including cisplatin, alone or in combination with other chemotherapies, have been shown to be active in patients with metastatic melanoma. Additionally, it is known that cisplatin, an alkylating agent known to inhibit DNA synthesis of dividing cells, triggers increased intracellular level of p53. The synergistic effects of cisplatin and ALT-801 treatment may induce cisplatin-mediated increases in p53 peptide display on the tumors and subsequently enhance tumor targeting of ALT-801.

May be safely tapered off anti-hypertensives if currently on anti-hypertensives

New York Heart Association classification I or II

No congestive heart failure <6 months

No unstable angina pectoris <6 months

No myocardial infarction <6 months

No history of ventricular arrhythmias

Normal cardiac stress test required if any of the following is present:

Age ≥ 50

History of abnormal EKG

Symptoms of cardiac ischemia or arrhythmia

Pulmonary

Normal pulmonary function test (FEV1 ≥ 70% of predicted value) if any of the following is present:

Prolonged history of cigarette smoking

Symptoms of respiratory dysfunction

Other

No known autoimmune disease

No known HIV positive

No psychiatric illness/social situations that would limit study compliance

No history or evidence of CNS disease

No active systemic infection requiring parental antibiotic therapy

No systemic steroid therapy required

No prior organ allograft or allogeneic transplantation

Not receiving chronic medication for asthma

Not pregnant or nursing

Fertile patients must use effective contraception

Contacts and Locations

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01029873